Recent estimates suggest that the prevalence of lymphedema in developed countries is as high as 1.44 per thousand persons. Consequences of the disease include an increase in chronic pain and fatigue, higher incidence of dermal infections, severe anxiety and depression, a 10 year decrease in life expectancy with doubled health care costs. Yet in spite of the growing burden of this disease, clinical options available fr most suffering patients are the same today as 30 years ago: namely proper skin care and various methods of tissue compression. Such approaches have the goal of reducing symptomatic severity, while failing to understand or correct the underlying dysfunction. Lymphatic function is highly sensitive to the forces imposed on the vessels, and lymphedema drastically alters the local mechanical environment of the interstitium surrounding lymphatics through substantial collagen and lipid accumulation. A comprehensive understanding of the crosstalk between this environment and lymphatic function, particularly in the context of lymphedema, would therefore have significant clinical benefits not only for patients suffering from lymphedema, but also for patients with other diseases where lymphatics have been implicated, such as impaired immune cell trafficking, severe obesity, atherosclerosis, and cancer metastasis. The objective of this project is to develop a predictive framework that quantitatively describes the interplay between mechanical loading, lymphatic growth and remodeling, and lymphatic function by using experimental approaches at the animal, tissue and cellular levels. Our central hypothesis is that sustained abnormally elevated mechanical loading on a collecting lymphatic vessel induces a remodeling response by the vessel, which promotes cell proliferation and increased matrix deposition until it reaches a threshold at which this response negatively affects lymphatic transport, altering the tissue microenvironment and further compromising fluid, protein, and lipid transport by the lymphatic system. This hypothesis will be tested through two Specific Aims: 1) Quantify the growth and remodeling response of the lymphatic microstructure to sustained mechanical loading; and 2) Quantify the effects of this growth and remodeling response on lymphatic function and vessel mechanics. The rationale for this work is that it will provide mechanistic insight into the progression of lymphedema, identifying pathways for intervention that will restore lymphatic function. We anticipate that the findings from these studies will have an impact on the treatment of lymphatic disease by paving the way for patient specific modeling and for prediction of lymphedema risk through the use of integrated lymphatic imaging and computational modeling toolsets.